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Reducing Clozapine-Related Morbidity and Mortality: 5 Years of Experience With the Clozaril National Registry

Gilbert Honigfeld, Ph.D., Felix Arellano, M.D., Jitender Sethi, Ph.D., Anthony Bianchini, and Jeffrey Schein, Dr.P.H., M.P.H.

Published: January 1, 1998

Article Abstract

The Clozaril National Registry (CNR) was created to help protect patients from developing potentiallyfatal agranulocytosis secondary to treatment with the antipsychotic medicine clozapine. TheCNR, designed and maintained by the manufacturer of the branded Clozaril (clozapine), has the principalgoals of (1) prophylaxis—preventing inappropriate retreatment, and (2) quality assurance—overseeing adherence to a "no blood, no drug" policy. This article reviews the estimated impact of theCNR on clozapine-related morbidity and mortality over the first 5 years of commercial experience inthe United States. Method: Complete data on leukopenia and agranulocytosis, gathered from the CNRdatabase for the period of 1990-1994, were reviewed and compared with data from the pre-CNR period.Results: Use of clozapine in 99,502 patients according to package labeling requirements (distributionof the medicine linked to mandated white blood cell count testing) was associated with a total of382 cases of agranulocytosis (0.38%) versus an expected cumulative total of 995 cases (based on thepre-CNR rate of 1% to 2%). Based on the expected agranulocytosis rate, up to 149 deaths might havebeen anticipated. Instead, there were only 12 deaths attributed to complications of agranulocytosis.Conclusion: The CNR provides for universal rechallenge protection as well as controlled dispensingof clozapine. It also serves as an early warning system to promote the safe and effective use of clozapine.The CNR includes quality assurance mechanisms designed to enhance compliance. Despite theadded logistic requirements this system places upon physician, pharmacist, and manufacturer, theCNR has helped to reduce substantially potential fatal outcomes. The CNR reinforces both patient andtreatment system compliance. Based on this favorable experience concerning agranulocytosis and associatedfatalities, the Neuropsychopharmacology Advisory Committee to the U.S. Food and DrugAdministration has unanimously recommended a reduction in frequency of the white blood cell counttesting requirement after 6 months to every 14 days, instead of weekly. Finally, the CNR databasecontaining white blood cell count and demographic data on every patient in the United States who hasreceived the medicine has served as a unique epidemiologic database.

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Volume: 59

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